Laboratory Studies

Any child with a presumed diagnosis of neuroblastoma or any other childhood cancer should be referred to a pediatric cancer center for proper care and evaluation. Laboratory studies should include the following:

A one-week-old neonate had abdominal ultrasonography for evaluation of projectile vomiting. A right adrenal mass (100% cystic) was an incidental finding. Evaluation of the mass by CT was consistent with an adrenal bleed (3.6 x 3.1 x 2.4 cc). The infant was followed at 2 weeks (2-dimensional size diminished to 1.5 x. 2.4 cm2 on ultrasonography) and then at 6 weeks to document that the adrenal bleed continued to involute. Urine catecholamines were normal.

In cases of paraspinal masses, MRI aids in determining the presence of intraspinal tumor and cord compression. Horner syndrome should be evaluated with an MRI of the neck and head. See the image below.

MRI of a left adrenal mass. The mass was revealed by fetal ultrasonography at 30 weeks' gestation. During infancy, the mass was found on the inferior pole of the left adrenal and was completely resected. Before surgery, the metastatic workup was negative. Surgical pathology service confirmed a diagnosis of neuroblastoma. After 3 years of follow-up care, no recurrence was observed.

I
123/131 -methyliodobenzylguanadine (MIBG) accumulates in catecholaminergic cells and provides a specific way of identifying primary and metastatic disease if present. Increasing numbers of institutions have access to MIBG scanning.

A technetium-99 bone scan can also be used to evaluate bone metastases. This may be especially helpful in patients with negative MIBG study findings. Most current therapeutic protocols require both a bone scan and MIBG scan.

Skeletal surveys may also be useful, especially in patients with multiple metastatic lesions.

Positron emission tomography (PET) scan are under evaluation but are not currently recommended as part of the radiographic workup.

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Other Tests

Obtain the following as baseline studies before therapy with anthracyclines:

Procedures

Bilateral bone marrow aspirates and biopsies should be performed to exclude metastatic disease.

Biopsy or resection of the primary tumor (stage I or II disease) is performed to collect tissue samples for biologic studies used to assign the patient into the appropriate risk category. Most centers in the United States perform limited open biopsies when the primary tumor is unresectable upfront. Adequate tissue is needed to perform molecular studies that aid in risk assignment. Extensive resections should be avoided upfront if they may place patient at excessive risk from morbidity or mortality from surgery. Neuroblastoma is a chemo-sensitive tumor; thus, second-look surgery to resect a residual primary may be a safer procedure with biopsy only performed upfront.

Tissue samples from a primary or metastatic tumor may be undifferentiated and confused with other small, round, blue cell tumors of childhood; however, immunohistochemical stains can aid with tissue diagnosis.

Molecular techniques, such as fluorescent in situ hybridization (FISH), can detect MYCN amplification, an important prognostic marker. Polymerase chain reaction (PCR) can identify specific translocations, such as t(11;22), in Ewing sarcoma and t(2;13) in alveolar rhabdomyosarcoma, thus ruling out neuroblastoma.

Neuroblastoma in bone marrow can be difficult to distinguish from other small, round, blue cell tumors of childhood.

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Histologic Findings

Biopsy findings are usually required to diagnose neuroblastoma. Depending on the extent of disease at presentation, consider complete surgical resection, especially in patients with low-stage disease. Even without a biopsy, the presence of elevated urinary catecholamines and a bone marrow aspirate or biopsy with unequivocal neuroblastoma cells is diagnostic.

Histologically, neural crest tumors can be classified as neuroblastoma, ganglioneuroblastoma, and ganglioneuroma, depending on the degree of maturation and differentiation of the tumor. Undifferentiated neuroblastomas histologically present as small, round, blue cell tumors with dense nests of cells in a fibrovascular matrix and Homer-Wright pseudorosettes. These pseudorosettes, observed in 15-50% of tumor samples can be described as neuroblasts surrounding eosinophilic neuritic processes. The typical tumor shows small uniform cells with scant cytoplasm and hyperchromatic nuclei. A neuritic process, also called neuropil, is a pathognomonic feature of neuroblastoma.

The pathologist must thoroughly evaluate the tumor because regions with different gross appearance may exhibit a different histology.

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Staging

The patient should undergo a staging workup along with surgical resection or biopsy, as appropriate. Using various molecular features in conjunction with pathology and staging is essential to appropriately stratify patients and determine the best therapy.

The International Neuroblastoma Staging System (INSS) is currently used in all cooperative group studies in the United States. Recently, the International Neuroblastoma Risk Group Staging System (INRGSS) and International Neuroblastoma Risk Group Consensus Pretreatment Classification were released.
[16] The current INSS system is based on degree of surgical resection and thus is not appropriate for use with the INRG Pretreatment Classification. This is especially important because not all groups use upfront surgical resection as part of their staging system. The INRG was formulated to be used in international settings and to facilitate comparison of treatment outcomes across studies to allow common definitions among all groups. Thus, development of the INRGSS was facilitated using pretreatment tumor imaging rather than extent of surgical resection.

The INRGSS is as follows:

L1 - Localized tumor not involving vital structures, as defined by the list of image-defined risk factors and confined to one body component

L2 - Locoregional tumor with presence of one or more image-defined risk factors

Berthold F, Baillot A, Hero B, et al. Which cases are found and missed by neuroblastoma screening at 1 year? Results from the 1992 to 1995 study in three Federal States of Germany. J Clin Oncol. 1999 Apr. 17(4):1200. [Medline].

CT scan of abdomen in a patient with a retroperitoneal mass arising from the upper pole of the left kidney and elevated urine catecholamines.

MRI of a left adrenal mass. The mass was revealed by fetal ultrasonography at 30 weeks' gestation. During infancy, the mass was found on the inferior pole of the left adrenal and was completely resected. Before surgery, the metastatic workup was negative. Surgical pathology service confirmed a diagnosis of neuroblastoma. After 3 years of follow-up care, no recurrence was observed.

A one-week-old neonate had abdominal ultrasonography for evaluation of projectile vomiting. A right adrenal mass (100% cystic) was an incidental finding. Evaluation of the mass by CT was consistent with an adrenal bleed (3.6 x 3.1 x 2.4 cc). The infant was followed at 2 weeks (2-dimensional size diminished to 1.5 x. 2.4 cm2 on ultrasonography) and then at 6 weeks to document that the adrenal bleed continued to involute. Urine catecholamines were normal.

Table. A Consensus Pretreatment Classification schema by the International Neuroblastoma Risk Group (INRG). This schema is based in the INRG stage, age, histologic category, tumor grade of differentiation, MYCN sastus, 11q-aberrations and DNA ploidy. A combination of these characteristics results in four risk groups noted in the last column: very low, low, intermediate and high risk, with the following 5 year EFS: >85%, >75%-85%, >50%-75%, and &lt; 50%. These risk groups are distributed among the different stages and labeled alphabetically from A to R (without letters L and M to avoid confusion with the INRG stage notation). Notations in the table are as follow: L1, localized tumor confined to one body compartment; L2, locoregional tumor with presence of one or more risk factors defined radiologically; M, distant metastatic disease (except stage MS); MS, metastatic disease confined to skin, liver and/or bone marrow in children &lt; 18 months of age. GN, ganglioneuroma; GNB, ganglioneuroblastoma; Amp, amplified; n/amp, not amplified. (Adapted from The International Neuroblastoma Risk Group (INRG) Classifications System: An INRG Task Force Report by Cohn, et al. Journal of Clinical Oncology 27(2):289-297, 2009).